MUC1 in macrophage contributions to cigarette smoke-induced lung cancer
Menée in vitro et in vivo, cette étude met en évidence des mécanismes de nature inflammatoire par lesquels la protéine MUC1 contribue au développement d'un cancer du poumon induit par le tabagisme
Expression of the pro-oncogenic mucin MUC1 is elevated by inflammation in airway epithelial cells, but the contributions of MUC1 to the development of lung cancer are uncertain. In this study, we developed our finding that cigarette smoke (CS) increases Muc1 expression in lung macrophages, where we hypothesized it might contribute to CS-induced transformation of bronchial epithelial cells. In human macrophages, CS extract (CSE) strongly induced MUC1 expression through a mechanism involving the nuclear receptor PPAR-γ. CSE-induced ERK activation was also required for MUC1 expression, but it had little effect on MUC1 transcription. RNAi-mediated attenuation of MUC1 suppressed CSE-induced secretion of TNF-α from macrophages, by suppressing the activity of the TNF-α processing enzyme TACE, arguing that MUC1 is required for CSE-induced and TACE-mediated TNF-α secretion. Similarly, MUC1 blockade after CSE inducion through suppression of PPAR-γ or ERK inhibited TACE activity and TNF-α secretion. Conditioned media from CSE-treated macrophages induced MUC1 expression and potentiated CSE-induced transformation of human bronchial epithelial cells (HBEC) in a TNF-α-dependent manner. Together, our results identify a signaling pathway involving PPAR-γ, ERK and MUC1 that is used by CSE to trigger TNF-α secretion from macrophages. Further, our results show how that MUC1 contributes to smoking-induced lung cancers that are driven by inflammatory signals driven by macrophages.
Cancer Research 2013